# Uncovering sex-specific differences in ASH1L-disease > **NIH NIH R21** · BROWN UNIVERSITY · 2024 · $258,620 ## Abstract PROJECT SUMMARY Autism spectrum disorder (ASD) affects 1 in 36 people and is a highly heterogeneous condition that has limited therapeutic interventions and affects males more often than females. Similarly other disorders like Attention deficit hyperactive (ADHD), Tourette syndrome (TS) and Schizophrenia (SCZ) have sex-specific differences in their prevalence and clinical presentation. However, the precise cellular and molecular mechanisms that underlie sex-specific dimorphisms associated these neuropsychiatric disorders are understudied. Our long- term goal is to define the mechanisms that underlie sex-specific differences related to neuropsychiatric disorders. Human genetics studies have identified high risk variants in genes that encode chromatin regulatory factors associated with ASD, TS, ADHD, and SCZ. Our studies focus on the histone methyltransferase ASH1L which has been identified as a gene of high importance that raises above genome wide significance in large sequencing studies of ASD, TS and SCZ. We find that boys with mutations in ASH1L present more often with ASD and ADHD, while girls with ASH1L mutations are more likely to present seizures. However, the molecular mechanisms underlying sex-specific differences associated with deficits in ASH1L are unknown. We developed a high-risk, high-reward research program that brings together in-depth clinical neuro-phenotyping and stem cell pre-clinical studies to uncover mechanisms underlying sex-specific differences associated with mutations in ASH1L. Our Central hypothesis is that ASH1L modulates transcriptional programs that govern neuronal structure and function, and that sex-specific post-translational histone modifications lead to genome- wide alteration of molecular programs that underlie male and female phenotypic differences in ASH1L related disorders. We will test this hypothesis in the following specific aims: Aim-1 will define the phenotypic diversity and severity of neurological presentations associated with ASH1L disease with respect to sex-specific differences. Aim 2 will define sex-specific cellular and molecular phenotypes caused by ASH1L dysregulation in human neurons derived from male and female individuals with ASH1L mutations. The impact of our work is that defining the clinical diversity and severity of ASH1L neurological phenotypes in a male and female specific manner will be important for patients, families, and their physicians with respect to medical treatment. Our work with patients, will allow us to uncover sex-specific differences clinically and mechanistically using patient iPSC-derived neurons, which will allow us to identify targets for therapeutic interventions. Finally, our work will also allow us to begin to prepare the ASH1L patient community for larger scale clinical studies. ## Key facts - **NIH application ID:** 10879570 - **Project number:** 1R21MH136643-01 - **Recipient organization:** BROWN UNIVERSITY - **Principal Investigator:** Judy Shih-Hwa Liu - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $258,620 - **Award type:** 1 - **Project period:** 2024-06-05 → 2026-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10879570 ## Citation > US National Institutes of Health, RePORTER application 10879570, Uncovering sex-specific differences in ASH1L-disease (1R21MH136643-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879570. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*